Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels

ABSTRACT

Pharmaceutically acceptable hydrogel polymers of natural, recombinant or synthetic origin, or hybrids thereof, are introduced in a dry, less hydrated, or substantially deswollen state and rehydrate in a physiological environment to undergo a volumetric expansion and to affect sealing, plugging, or augmentation of tissue, defects in tissue, or of organs. The hydrogel polymers may deliver therapeutic entities by controlled release at the site. Methods to form useful devices from such polymers, and to implant the devices are provided.

FIELD OF THE INVENTION

[0001] This invention relates to making and using medically usefularticles formed from hydrogels. More specifically, the present inventionrelates to the methods of using in situ hydration of hydrogel articlesto seal or augment tissues or organs.

BACKGROUND OF THE INVENTION

[0002] Hydrogels are materials that absorb solvents (such as water),undergo rapid swelling without discernible dissolution, and maintainthree-dimensional networks capable of reversible deformation. See, e.g.,Park, et al., Biodegradable Hydrogels for Drug Delivery, Technomic Pub.Co., Lancaster, Pa. (1993).

[0003] Hydrogels may be uncrosslinked or crosslinked. Uncrosslinkedhydrogels are able to absorb water but do not dissolve due to thepresence of hydrophobic and hydrophilic regions. A number ofinvestigators have explored the concept of combining hydrophilic andhydrophobic polymeric components in block (Okano, et al., “Effect ofhydrophilic and hydrophobic microdomains on mode of interaction betweenblock polymer and blood platelets”, J. Biomed. Mat. Research, 15:393-402(1981), or graft copolymeric structures (Onishi, et al., in ContemporaryTopics in Polymer Science, (Bailey & Tsuruta, Eds.), Plenum Pub. Co.,New York, 1984, p. 149), and blends (Shah, “Novel two-phase polymersystem,” Polymer, 28:1212-1216 (1987) and U.S. Pat. No. 4,369,229 toShah) to form the “hydrophobic-hydrophilic” domain systems, which aresuited for thermoplastic processing. See, Shah, Chap. 30, in WaterSoluble Polymers (Shalaby et al., Eds.), Vol. 467, ACS-Symp. Ser., Amer.Chem. Soc., Washington (1991). These uncrosslinked materials can formhydrogels when placed in an aqueous environment.

[0004] Hydrogels may be formed by physical or chemical crosslinking, ora combination of these two processes. Physical crosslinking takes placeas a result of ionic linkages, hydrogen bonding, Van der Waals forces,or other such physical forces. Chemical crosslinking occurs due to theformation of covalent linkages. Covalently crosslinked networks ofhydrophilic polymers, including water-soluble polymers are traditionallydenoted as hydrogels (or aquagels) in the hydrated state. Hydrogels havebeen prepared based on crosslinked polymeric chains ofmethoxypoly(ethylene glycol) monomethacrylate having variable lengths ofthe polyoxyethylene side chains, and their interaction with bloodcomponents has been studied (Nagaoka et al., in Polymers as Biomaterial(Shalaby et al., Eds.) Plenum Press, 1983, p. 381). A number of aqueoushydrogels have been used in various biomedical applications, such as,for example, soft contact lenses, wound management, and drug delivery.

[0005] The concept of injecting hydrogels to fill spaces or tracks isdescribed in U.S. Pat. No. 5,645,583 to Villain et al. That patentdescribes a polyethylene oxide gel implant that may be injected into ahuman body for tissue replacement and augmentation. U.S. Pat. No.5,090,955 to Simon describes the use of gels in ophthalmology forcorneal tissue augmentation procedures such as Gel Injection AdjustableKeratoplasty (GIAK). Neither patent mentions of augmentation of suchtissue by hydration and swelling-induced shape changes in the tissue.Instead, for example, the Simon patent describes “smoothing andmassaging” of the cornea to remove excess hydrogel material.

[0006] Non-degradable hydrogels made from poly(vinyl pyrrolidone) andmethacrylate have been fashioned into fallopian tubal occluding devicesthat swell and occlude the lumen of the tube. See, Brundin, “Hydrogeltubal blocking device: P-Block”, in Female Transcervical Sterilization,(Zatuchini et al., Eds.) Harper Row, Philadelphia (1982), pp. 240-244.Because such hydrogels undergo a relatively small amount of swelling andare not absorbable, so that the sterilization is not reversible, thedevices described in the foregoing reference have found limited utility.

[0007] U.S. Pat. No. 5,324,775 to Rhee et al. describes injectableparticles based on swellable natural polymers that may be suspended in anon-aqueous fluid, e.g., an oil. The particles are formed from groundsolid articles and may be injected into soft tissue to rehydrate in-situto augment the tissue. A significant drawback of the compositionsdescribed in that patent, however, is the requirement that a non-aqueousand water insoluble carrier be used to inject the particles.

[0008] In view of the foregoing, it would be desirable to providemethods of using hydrogel materials, for example, for temporaryocclusion of a body lumen or for tissue augmentation, that overcome thedrawbacks of previously known compositions and methods.

[0009] It therefore would be desirable to provide methods of forming andusing medically useful articles that comprise absorbable hydrogels,capable of undergoing a relatively large degree of swelling in-situ.

[0010] In addition to tissue augmentation and lumen occlusion,absorbable hydrogel articles may have application in sealing surgicallycreated voids. For example, tissue biopsy is a very commonly performedminor surgical procedure, and is often to confirm or rule out thepresence of disease that has been identified by a previously undertakendiagnostic modality, e.g., X-rays or ultrasound imaging.

[0011] Often needle biopsies are performed on solid organs using needlesthat are introduced from the outside of the patient's body, across thepelvic or thoracic wall. Visualization in performing such procedures istypically limited and the cutting action of the needle often generatesassociated complications subsequent to the biopsy. Increasing experiencewith percutaneous biopsy has clarified some subtle points andcontroversies about possible complications and their prevention.

[0012] For example, while hemorrhage is possible with even the smallestaspiration needle, the risk has generally been assumed to increasesignificantly with the use of larger cutting needles and/or in patientswith coagulation deficiencies. Some argue that the benefits attainedwith the use of cutting needles therefore is not worth the added risk.Unfortunately, while fine-needle aspiration techniques may provide thenecessary tissue for cytologic diagnosis in many cases, there aresituations in which cutting needles are needed for optimal diagnosticaccuracy, such as biopsy of the retroperitoneum (when lymphoma is likelyand must be typed) and in the diagnosis of unusual neoplasms, benignneoplasms, or diffuse hepatic or renal parenchymal diseases.

[0013] Even though needle biopsy is widely regarded as safe, often timesleaks may develop in the underlying tissues due to the needle puncture.For example, when conducting a needle biopsy of the lung, air leaks maydevelop, leading to collapse of the lung and/or pneumothorax. Theincidence of clinically significant pneumothorax following needle biopsyhas been reported to be in the 15-25% range. Needle biopsy also is usedto assess whether kidney transplantation has been successful, and isassociated with the formation of arteriovenous fistulae in 10-15% ofcases. Likewise, biopsy of the liver and spleen lead to bleedingcomplications in 5-10% of cases.

[0014] Liver biopsy is essential to the management of liver diseases.Although generally safe, the presence of a vascular tumor, bleedingdiathesis or ascites makes the procedure more hazardous. The developmentof transvenous hepatic biopsy techniques have been one response to thisproblem. Prevention of hemorrhagic complications in high-risk patientshas been accomplished with different clinical methods, and with varyingdegrees of success. Several authors have suggested use of a transjugularroute for biopsy of the liver in high-risk patients. More recently,others have suggested that cutting needles may be used in conjunctionwith various methods to plug the needle track, for example, with steelembolization coils or gelatin sponge particles, such as GELFOAM®,manufactured by Upjohn, Inc., Kalamazoo, Mich.

[0015] U.S. Pat. No. 5,522,898 to Bao describes a closure device for therepair of skin tissue, controlling bleeding, and reducing the likelihoodof inducing excess scar tissue during a routine skin biopsy procedure,using a cylindrical tube made from a foam material which is absorbed ina biopsy site with little tissue reaction. That patent also describesthe use of GELFOAM® for topical applications. While GELFOAM® may beeffective in preventing bleeding, the sponge has a particulatestructure, and is difficult to inject smoothly down a needle track. Therisk of clumping and the subsequent scarcity of sponge along the needletrack presents a risk of bleeding after non-uniform embolization.

[0016] Chisholm et al., in “Fibrin Sealant as a Plug for the Post LiverBiopsy Needle Track,” Clinical Radiology, 40:627-628 (1989) propose theuse of fibrin sealants to embolize a needle track. A drawback of thistechnique, however, is that fibrin sealants are associated with atheoretical risk of disease transmission due to the human and animalproteins that are the constituents of fibrin sealants.

[0017] Needle biopsies of other parenchymal tissues, such as kidney orlung tissue, also often result in prolonged hemorrhage or airleak fromthe site of the biopsy. This especially may present a problem whenmultiple biopsies are to be obtained from a particular organ.

[0018] It therefore would be desirable to provide hydrogel articles andmethods for plugging voids created in tissue during surgical procedures,such as a needle track created during a biopsy, so as to reduce the riskof hemorrhage after tissue removal.

[0019] Abusafieh et al., in “Development of Self-Anchoring BoneImplants. I. Processing and Material Characterization,” J. Biomed MaterRes., 38:314-327 (1997) describe the development of a self anchoringbone implant formed by polymerizing hydrogels around carbon and KEVLAR®fibers, a registered trademark of E.I. DuPont de Nemours, Inc.,Wilmington, Del. The concept of self-anchoring swelling-type orthopedicimplants is described by Greenberg et al. in “Stimulation of BoneFormation by a Swelling Endosseous Implant,” J. Biomed Mater Res.,12:922-933 (1978). Such implants would, in principle, dilate in acontrolled manner by absorption of body fluids to achieve fixation by anexpansion-fit mechanism.

[0020] Although research on swelling-type bone implants began more than15 years ago, exploitation of this concept has been largely hampered bythe inability to produce a material with the desired hydromechanicalproperties. None of the previously known materials are made fromabsorbable hydrogels and all are essentially permanent implants. Also,because there is a degradation in mechanical properties that accompaniesswelling, hydration for such materials has been restricted to less than5-8% by weight and takes place over long periods of time (several days).Since these previous known implants were intended for load bearingapplications, low hydration rates clearly were undesirable.

[0021] It therefore also would be desirable to provide methods of usingand forming hydrogel articles that hydrate relatively quickly, andwithout substantial degradation of mechanical properties.

SUMMARY OF THE INVENTION

[0022] In view of the foregoing, it is an object of the presentinvention to provide methods of using hydrogel articles for sealing oroccluding a body lumen, or tissue augmentation, that overcome thedrawbacks of previously known devices and methods.

[0023] It is another object of this invention to provide methods ofusing and forming hydrogel articles capable of undergoing a relativelylarge degree of swelling in-situ.

[0024] It is a further object of the present invention to providemethods of using and forming hydrogel articles for plugging voidscreated in tissue during surgical procedures, such as a needle trackcreated during a biopsy, so as to reduce the risk of hemorrhage aftertissue removal.

[0025] It is yet another object of this invention to provide methods ofusing and forming hydrogel articles that hydrate relatively quickly, andwithout substantial degradation of mechanical properties.

[0026] These and other objects of the invention are accomplished byproviding methods of using and forming medical articles frompharmaceutically acceptable hydrogel polymer, wherein the articles areintroduced in a dry, less hydrated, or substantially deswollen state,and rehydrate in a physiological environment to increase in volume. Themethods of the present invention may be advantageously used to affectsealing, plugging, or augmentation of tissue, defects in tissue andorgans, and may optionally permit controlled release of therapeuticagents at an implantation site. Hydrogel polymers useful for the presentinvention may be bioabsorbable or biostable, preferably exhibit arelatively large degree of swelling and rapid rehydration rate, and mayinclude any of a variety of pharmaceutically acceptable or implantablehydrogel biomaterials of natural, recombinant, or of synthetic origin orhybrids thereof.

[0027] Methods to form medically useful devices in-situ, and to implantdevices in accordance with the principles of the present invention in aminimally invasive fashion, also are provided.

DETAILED DESCRIPTION OF THE INVENTION

[0028] In accordance with the present invention one or more rods, plugs,crushed or irregularly shaped pieces of substantially dehydratedhydrogel material are introduced into a lumen or void in a patient'sbody to seal or plug a biopsy needle track, serve to reinforce weaktissue, or deliver a therapeutic compound. The hydrogel polymerpreferably rehydrates rapidly, within a few minutes of being placed in amoist tissue environment, so as to anchor itself within tissue. Duringthe hydration process, the dried gel may expand volumetrically, e.g., inone, two or three dimensions, to several times its original size,thereby lodging the gel within the tissue and sealing against leakage offluids through the tissue.

[0029] This written description comprises the following portions: adescription of hydrogels suitable for use in practicing the methods ofthe present invention, descriptions of medical articles and methods forusing the hydrogel articles of the present invention; and, examplecompositions of hydrogel articles and exemplary applications.

[0030] I. Hydrogel Materials Suitable For Use In The Invention

[0031] Hydrogels may be formed from covalently or non-covalentlycrosslinked materials, and may be non-degradable (“biostable”) in aphysiological environment or broken down by natural processes within thebody, referred to as biodegradable or bioabsorbable. The breakdownprocess may be due to one of many factors in the physiologicalenvironment, such as enzymatic activity, heat, hydrolysis, or others,including a combination of these factors.

[0032] Hydrogels that are crosslinked may be crosslinked by any of avariety of linkages, which may be reversible or irreversible. Reversiblelinkages may be due to ionic interaction, hydrogen or dipole typeinteractions or the presence of covalent bonds. Covalent linkages forabsorbable or degradable hydrogels may be chosen from any of a varietyof linkages that are known to be unstable in an animal physiologicalenvironment due to the presence of bonds that break either by hydrolysis(e.g., as found in synthetic absorbable sutures), enzymatically degraded(e.g., as found in collagen or glycosamino glycans or carbohydrates), orthose that are thermally labile (e.g., azo or peroxy linkages).

[0033] All of the hydrogel materials appropriate for use in the presentinvention should be physiologically acceptable and should be swollen inthe presence of water. These characteristics allow the hydrogels to beintroduced into the body in a “substantially deswollen” state and over aperiod of time hydrate to fill a void, a defect in tissue, or create ahydrogel-filled void within a tissue or organ by mechanically exerting agentle force during expansion. The hydrogel may be preformed or formedin situ.

[0034] “Substantially deswollen” is defined as the state of a hydrogelwherein an increase in volume of the hydrogel of the article or deviceformed by such hydrogel is expected on introduction into thephysiological environment. Thus, the hydrogel may be in a dry state, orless than equilibrium hydrated state, or may be partially swollen with apharmaceutically acceptable fluid that is easily dispersed or is solublein the physiological environment. The expansion process also may causethe implanted material to become firmly lodged within a hole, anincision, a puncture, or any defect in tissue which may be congenital,diseased, or iatrogenic in origin, occlude a tubular or hollow organ, orsupport or augment tissue or organs for some therapeutic purpose.

[0035] Hydrogels useful in practicing the present invention may beformed from natural, synthetic, or biosynthetic polymers. Naturalpolymers may include glycosminoglycans, polysaccharides, proteins etc.The term “glycosaminoglycan” is intended to encompass complexpolysaccharides which are not biologically active (i.e., not compoundssuch as ligands or proteins) and have repeating units of either the samesaccharide subunit or two different saccharide subunits. Some examplesof glycosaminoglycans include dermatan sulfate, hyaluronic acid, thechondroitin sulfates, chitin, heparin, keratan sulfate, keratosulfate,and derivatives thereof.

[0036] In general, the glycosaminoglycans are extracted from a naturalsource and purified and derivatized. However, they also may besynthetically produced or synthesized by modified microorganisms such asbacteria. These materials may be modified synthetically from a naturallysoluble state to a partially soluble or water swellable or hydrogelstate. This modification may be accomplished by various well-knowntechniques, such as by conjugation or replacement of ionizable orhydrogen bondable functional groups such as carboxyl and/or hydroxyl oramine groups with other more hydrophobic groups.

[0037] For example, carboxyl groups on hyaluronic acid may be esterifiedby alcohols to decrease the solubility of the hyaluronic acid. Suchprocesses are used by various manufacturers of hyaluronic acid products(such as Genzyme Corp., Cambridge, Mass.) to create hyaluronic acidbased sheets, fibers, and fabrics that form hydrogels. Other naturalpolysaccharides, such as carboxymethyl cellulose or oxidized regeneratedcellulose, natural gum, agar, agrose, sodium alginate, carrageenan,fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gumghatti, gum karaya, gum tragacanth, locust beam gum, arbinoglactan,pectin, amylopectin, gelatin, hydrophilic colloids such as carboxymethylcellulose gum or alginate gum cross-linked with a polyol such aspropylene glycol, and the like, also form hydrogels upon contact withaqueous surroundings.

[0038] Synthetic polymeric hydrogels generally swell or expand to a veryhigh degree, usually exhibiting a 2 to 100-fold volume increase uponhydration from a substantially dry or dehydrated state. Synthetichydrogels may be biostable or biodegradable or bioabsorbable. Biostablehydrophilic polymeric materials that form hydrogels useful forpracticing the present invention include poly(hydroxyalkylmethacrylate), poly(electrolyte complexes), poly(vinylacetate)cross-linked with hydrolysable bonds, and water-swellable N-vinyllactams.

[0039] Other suitable hydrogels include hydrophilic hydrogels know asCARBOPOL®, a registered trademark of B.F. Goodrich Co., Akron, Ohio, foracidic carboxy polymer (Carbomer resins are high molecular weight,allylpentaerythritol-crosslinked, acrylic acid-based polymers, modifiedwith C10-C30 alkyl acrylates), polyacrylamides marketed under theCYANAMER® name, a registered trademark of Cytec Technology Corp.,Wilmington, Del., polyacrylic acid marketed under the GOOD-RITE® name, aregistered trademark of B. F. Goodrich Co., Akron, Ohio, polyethyleneoxide, starch graft copolymers, acrylate polymer marketed under theAQUA-KEEP® name, a registered trademark of Sumitomo Seika Chemicals Co.,Japan, ester cross-linked polyglucan, and the like. Such hydrogels aredescribed, for example, in U.S. Pat. No. 3,640,741 to Etes, U.S. Pat.No. 3,865,108 to Hartop, U.S. Pat. No. 3,992,562 to Denzinger et al.,U.S. Pat. No. 4,002,173 to Manning et al., U.S. Pat. No. 4,014,335 toArnold and U.S. Pat. No. 4,207,893 to Michaels, all of which areincorporated herein by reference, and in Handbook of Common Polymers,(Scott & Roff, Eds.) Chemical Rubber Company, Cleveland, Ohio.

[0040] Hydrogels also may be formed to be responsive to changes inenvironmental factors, such as pH, temperature, ionic strength, charge,etc., by exhibiting a corresponding change in physical size or shape,so-called “smart” gels. For example, thermoreversible hydrogels, such asthose formed of amorphous N-substituted acrylamides in water, undergoreversible gelation when heated or cooled about certain temperatures(lower critical solution temperature, LCST). Prevailing gel formationmechanisms include molecular clustering of amorphous polymers andselective crystallization of mixed phases of crystalline materials. Suchgels, which are insoluble under physiological conditions, alsoadvantageously may be used for practicing the present invention.

[0041] It is also possible to affect the rate at which a substantiallydehydrated hydrogel rehydrates in a physiological environment, such asencountered upon implantation in an animal. For example, creating aporous structure within the hydrogel by incorporating a blowing agentduring the formation of the hydrogel may lead to more rapid re-hydrationdue to the enhanced surface area available for the water front todiffuse into the hydrogel structure.

[0042] When a foamed gel is desired, a two component mixture of theprecursors to a hydrogel forming system may be selected such thatfoaming and polymerization to form the hydrogel are initiated when thetwo fluid channels are mixed. A double barrel syringe assembly may beprovided to mix the fluids, in which each barrel is equipped with aseparate plunger to force the material contained therein out through adischarge opening. The plungers preferably are connected to one anotherat the proximal ends so that a force exerted on the plungers generatesequal pressure within each barrel and displaces both plungers an equaldistance.

[0043] The hydrogel forming precursors for the foregoing system may beselected so that, for example, a free radical polymerization isinitiated when two components of a redox initiating system are broughttogether. One of these components additionally may include a foamingagent, e.g., sodium bicarbonate, that when exposed to an acidicenvironment (e.g., the other component in the syringe may comprise anacidic solution), releases carbon dioxide as a foaming agent. While theeffervescent compound reacts with the water-soluble acid to releasegases, the hydrogel structure is polymerizing and crosslinking, therebycausing the formation of a stable foamed gel. Alternatively, othertechniques, which are per se known, may be used to foam the hydrogels.

[0044] In addition, the driving force for water to penetrate adehydrated hydrogel also may be influenced by making the hydrogelhyperosmotic relative to the surrounding physiological fluids.Incorporation of charged species within hydrogels, for example, is knownto greatly enhance the swellability of hydrogels. Thus the presence ofcarboxyl or sulfonic acid groups along polymeric chains within thehydrogel structure may be used to enhance both degree and rate ofhydration. The surface to volume ratio of the implanted hydrogels alsois expected to have an impact on the rate of swelling. For example,crushed dried hydrogel beads are expected to swell faster to theequilibrium water content state than a rod shaped implant of comparablevolume.

[0045] Alternatively, instead of using dehydrated preformed hydrogels,in-situ formed hydrogels formed from aqueous solutions of precursormolecules also may be used. The hydrogels may be absorbable orbiostable. The precursor solutions preferably are selected so that thehydrogels when formed in the physiological environment are below theequilibrium level of hydration. Thus, when formed in-situ, the hydrogelshave the ability to hydrate and increase in size. If the hydrogels areformed in confined tissue spaces, the additional swelling is expected tofurther anchor the hydrogel in place.

[0046] Any of a variety of techniques may be used to form hydrogelsin-situ. For example, monomers or macromers of hydrogel formingcompositions may be further polymerized to form three dimensionallycross-linked hydrogels. The crosslinking may be covalent, ionic, and orphysical in nature. Polymerization mechanisms permitting in-situformation of hydrogels are per se known, and include, withoutlimitation, free radical, condensation, anionic, or cationicpolymerizations. The hydrogels also may be formed by reactions betweennucleophilic and electrophilic functional groups, present on one or morepolymeric species, that are added either simultaneously or sequentially.The formation of hydrogels also may be facilitated using external energysources, such as in photoactivation, thermal activation and chemicalactivation techniques.

Absorbable Polymeric Hydrogels

[0047] Absorbable polymers, often referred to as biodegradable polymers,have been used clinically in sutures and allied surgical augmentationdevices to eliminate the need for a second surgical procedure to removefunctionally equivalent non-absorbable devices. See, for example, U.S.Pat. No. 3,991,766 to Schmitt et al. and Shalaby, Encyclopedia ofPharmaceutical Technology (Boylan & Swarbrick, Eds.), Vol. 1, Dekker,New York, 1988, p. 465. Although these previously known devices wereintended for repairing soft tissues, interest in using such transientsystems, with or without biologically active components, in dental andorthopedic applications has grown significantly in the past few years.Applications of absorbable polymers are disclosed in Bhatia, et al., J.Biomater. Sci., Polym. Ed., 6 (5) :435 (1994), U.S. Pat. No. 5,198,220to Damani, U.S. Pat. No. 5,171,148 to Wasserman, et. al., and U.S. Pat.No. 3,991,766 to Schmitt et al.

[0048] Synthesis and biomedical and pharmaceutical applications ofabsorbable or biodegradable hydrogels based on covalently crosslinkednetworks comprising polypeptide or polyester components as theenzymatically or hydrolytically labile components, respectively, havebeen described by a number of researchers. See, e.g., Jarrett et al.,“Bioabsorbable Hydrogel Tissue Barrier: In Situ Gelation Kinetics,”Trans. Soc. Biomater., Vol. XVIII, 182 (1995); Sawhney et al.,“Bioerodible Hydrogels Based on PhotopolymerizedPoly(ethyleneglycol)-co-poly(α-hydroxy acid) Diacrylate Macromers”,Macromolecules, 26:581-587 (1993); Park, et al., Biodegradable HydroGelsfor Drug Delivery, Technomic Pub. Co., Lancaster, Pa. (1993); Park,“Enzyme-digestible swelling hydrogels as platforms for long-term oraldelivery: synthesis and characterization,” Biomaterials, 9:435-441(1988). The hydrogels most often cited in the literature are those madeof water-soluble polymers, such as polyvinyl pyrrolidone, which havebeen crosslinked with naturally derived biodegradable components such asthose based on albumin.

[0049] Totally synthetic hydrogels have been studied for controlled drugrelease and membranes for the treatment of post-surgical adhesion. Thosehydrogels are based on covalent networks formed by the additionpolymerization of acrylic-terminated, water-soluble polymers that haveat least one biodegradable spacer group separating the water solublesegments from the crosslinkable segments, so that the polymerizedhydrogels degrade in vivo. Such hydrogels are described in U.S. Pat. No.5,410,016, which is incorporated herein by reference, and may beparticularly useful for practicing the present invention.

[0050] Preferred hydrogels for use in the present invention are formedby the polymerization of macromers that form hydrogel compositions thatare absorbable in vivo. These macromers, for example, may be selectedfrom compositions that are biodegradable, polymerizable, andsubstantially water soluble macromers comprising at least one watersoluble region, at least one degradable region, and statistically morethan 1 polymerizable region on average per macromer chain, wherein thepolymerizable regions are separated from each other by at least onedegradable region.

[0051] Hydrogels that have some mechanical integrity and that cannot be“extruded” from the implantation site by forces applied by naturalmovement of surrounding tissues are preferred for this invention. Thus,hydrogels suitable for use in the present invention preferably arephysically or chemically crosslinked, so that they possess some level ofmechanical integrity even when fully hydrated. The mechanical integrityof the hydrogels may be characterized by the tensile modulus at breakingfor the particular hydrogel. Hydrogels having a tensile strength inexcess of 10 KPa are preferred, and hydrogels having a tensile strengthgreater than 50 KPa are more preferred.

[0052] II. Applications For In-Situ Hydration

[0053] A number of applications of the foregoing hydrogels are describedin accordance with the principles of the present invention. Moreparticularly, use of hydrogel medical articles are described fornumerous applications wherein the article inserted with a small profile,and upon hydration serves to occlude lumens, augment tissues or organs,or block orifices.

[0054] 1. Sealing of Biopsy Tracks

[0055] Biopsy needle tracks may be embolized in accordance with theprinciples of the present invention to reduce complications associatedwith needle biopsies, such as bleeding and airleaks. A preformed plug ofa hydrogel selected as described hereinabove may be placed in a needletrack, for example, using the same device that was used for the tissueretrieval.

[0056] Specifically, the hydrogel plug is formed from a materialexhibiting rapid hydration and swelling, and a low degree of syneresis,i.e., it does not allow absorbed fluid to be easily expelled undermoderate mechanical loading. The hydrogel plug may be preformed andpartially or completely dehydrated. Upon completion of a biopsy, thehydrogel plug is disposed in the needle track formed by the biopsyinstrument. The plug then rehydrates and swells to become firmly lodgedin the needle track. The hydrogel plug preferably is bioabsorbable, sothat it may be absorbed and allow tissue to eventually fill the needletrack. Alternatively, the hydrogel may be formed in-situ, as describedhereinabove.

[0057] 2. Bone Plugs

[0058] Bone plugs often are used to occlude the femoral canal during hipreplacement surgery. Restricting the escape of uncured bone cementduring the insertion of the femoral prosthesis is known to improvepenetration of the cement into adjacent spongy bone and ensure completefilling of the canal, including beneath the tip of the device. Pluggingthe medullary canal prior to cement insertion also aids in compactingthe bone cement to eliminate internal voids that may cause cracking andfailure of the cement. Apart from the initial cement insertion process,this application is not a load bearing one and is thus ideally suited tothe use of an absorbable hydrogel plug. After the cement has set up,within a few hours, the load is borne by the cement.

[0059] A rapidly hydrating hydrogel plug that has a “one size fits all”capability for intermedullary canals and that does not need any specialtools for insertion (drop fit only), may be a convenient tool fororthopedic surgeons. It is expected that a plug of substantiallydehydrated hydrogel material may be introduced into the intramedullarycanal after the reaming process is complete. The plug will rehydratewithin a few minutes to generate a fit sufficiently tight to preventleakage of the bone cement. Such bone plugs are expected to havesignificant benefits over previously known non-degradable polyethyleneplugs, which form permanent implants.

[0060] 3. Suture Anchors

[0061] Hydrogel articles prepared in accordance with the principles ofthe present invention may be advantageously employed as bone orcartilage anchors. Suture anchors play an increasingly important role inattaching tendons or ligaments to bone, and are typically made ofmetallic or other nonbioabsorbable materials. Non-loadbearingindications, such as delicate maxofacial reconstruction or repair ofcartilage tears, also may benefit from a soft hydrogel-type absorbablesuture anchor. The self hydrating and tightening characteristic ofhydrogels may advantageously reduce problems of anchor loosening,migration, interference with imaging studies, and the potentialrequirement for later implant removal.

[0062] For this and the preceding applications, hydrogel material may bethreaded or formed around nonabsorbable or absorbable polymer sutures toallow accurate guidance and placement of the devices. In thesubstantially dehydrated state the suture has a good holding or“potting” strength within the hydrogel article. Upon hydration of thehydrogel material, after the hydrogel is expected to be securelyanchored at the surgical site of interest, the suture material easilymay be removed. Sutures potted within the hydrogel articles may includesingle or composite fibers. The shape, form and diameter of the fibermay vary, and may include monofilament, multifilament, twisted thread,spun yarn, staple fiber and whisker.

[0063] 3. Dental Applications

[0064] Hydrogel articles of the present invention also may beadvantageously used in dentistry, for example, in occluding root canals.Generally, after a root canal has been cleaned and disinfected, theresulting passageway is occluded to prevent bacterial contamination.Often un-crosslinked rubber-type materials, such as Gutta-Percha, areused to plug these openings. Gutta-Percha, however, has no inherentform-fitting property and must be mechanically forced into the canal.

[0065] In accordance with the principles of the present invention, a rodof substantially dehydrated hydrogel material may be cut to size andintroduced into the root canal, where it is allowed to hydrate, swell,and lock into place to form a tight fit. The hydrogel is expected toprovide an effective barrier against oral fluids, food material, andbacteria. If a substantially non-degradable hydrogel is selected, longterm occlusion may be provided. Alternatively, an absorbable materialmay be used if it is desirable that natural tissues replace the hydrogelover a period of time.

[0066] 4. Wound Closure

[0067] Hydrogel articles of the present invention may be employed forclosure of percutaneous catheter puncture sites. Most angiographic,angioplasty, and a variety of other less-invasive catheter basedapproaches to the vascular system are carried out by cannulating thefemoral artery. Generally, a sheath is positioned through a puncturewound to provide access to the artery and allow exchange of variouscatheters required during a procedure. At the end of the procedure, thesheath is removed, often resulting in a considerable amount of bleeding.

[0068] In accordance with well-known techniques, manual pressure isapplied to the wound for a period of about 30 to 60 minuted to preventbleeding and allow cessation of bleeding by clot formation. Even when aclot has formed, the patient is not permitted to freely move around forfear of re-bleeding. Several medical devices, based on collagen-typematerials, have been developed to fill the space or track left by thesheath. These materials are however, inherently inflammatory andpro-thrombotic, and may promote intimal hyperplasia or thrombosis of theartery. While various suturing techniques have been developed that uselong needles, suture material, and knot pushing devices have been usedto close the arteriotomy site, these techniques require considerableskill, especially where visualization of the site is limited.

[0069] Hydrogel articles of the present invention may be advantageouslyused to overcome the drawbacks of previously known wound closuresystems. For example, a rod-shaped plug of a substantially desiccatedhydrogel may be deployed into the site of an arteriotomy and allowed tohydrate, in the presence of the tissue fluids and blood, to rapidly fillthe track of the catheter sheath and prevent further bleeding. Byswelling to equilibrium hydration, the plug will lock itself firmly inplace and thus reduce the risk of formation of a large hematoma at thesite of the puncture.

[0070] A hydrogel rod also may be used in conjunction with a pledgetconfigured for intraarterial placement, and that has a suture connectingit to the hydrogel rod. A pledget is a small thin resilient object,formed from polyester foam or felt, that is used to distribute a loadimposed by a suture strand to surrounding tissue to prevent tearing, orto reduce bleeding at a puncture site. In this case, the pledgetactually provides the arterial closure, but is anchored by the swollenhydrogel within the puncture site. The hydrogel itself may consist of asingle rod or alternatively, may comprise a combination of hydrogelshapes, such as braided strands, etc. In the latter case, the resultingmacroporous spaces and larger surface area are expected to permit morerapid hydration.

[0071] 5. Occlusion Of Arteriovenous Malformations

[0072] Hydrogel articles of the present invention may be introduced intoa patient's body in a low profile, substantially dehydrated state, suchthat upon hydration the hydrogel article occludes an abnormal vascularstructure. Abnormal vascular connections, known as arteriovenousmalformations (AVMs), may develop either as a congenital defect or as aresult of iatrogenic or other trauma. An AVM may lead to a substantialdiversion of blood from the intended tissue and may consequentlyengender a variety of symptoms, including those leading to morbidity.Subdural hematomas and bleeding also may occur as a result of thepresence of an AVM.

[0073] Surgical intervention is often undertaken to correct AVMs.Interventional radiologic approaches also are used to obliterate AVMs byembolization, in which the goal of embolization is to selectivelyobliterate an abnormal vascular structure, while preserving blood supplyto surrounding normal tissues. Embolization typically is accomplishedusing low-profile soft microcatheters that allow superselectivecatheterization into the brain to deliver an embolic material underfluoroscopic guidance. Various embolic materials have been used inendovascular treatment in the central nervous system, such ascyanoacrylates, ethylene-vinyl alcohol copolymer mixtures (EVAL),ethanol, estrogen, poly(vinyl acetate), cellulose acetate polymer, poly(vinyl alcohol) (PVA), gelatin sponges, microfibrillar collagen,surgical silk sutures, detachable balloons, and coils.

[0074] In accordance with the principles of the present invention,substantially dry hydrogel materials may be introduced with a catheterunder radiographic guidance to embolize AVMs. Upon delivery to thevascular network, the hydrogel articles, which may be in rod, pellet,fiber, rolled up film or other physical form, rehydrate and occlude thevascular flow by mechanical obstruction. Preferred hydrogel materials tobe used in this application should be biostable and not be degraded bythe vascular environment. Where permanent embolization is desired,non-degradable hydrogel materials are preferred over degradable ones.

[0075] 6. Occlusion Of Reproductive Organs

[0076] Hydrogel articles also may be introduced into the body in a lowprofile in a substantially dehydrated state such that, upon hydration,they occlude lumens of reproductive structures. For example, the WorldHealth Organization has underscored the need for a rapid and minimallyinvasive method for female sterilization. Most sterilization techniquesused currently are invasive and irreversible. Approximately 40-50% ofwomen age 15-44 that choose to use a contraceptive method are sterilizedor their husband has undergone sterilization.

[0077] Lack of reversibility and the need for a surgical procedure aremajor drawbacks of previously known sterilization methods. Ligation offallopian tubes must to be conducted under epidural anesthesia and is adifficult procedure to reverse. Recently developed scarificationtechniques involving off-label intrauterine use of Quinacrine have beenassociated with morbidity and even mortality. There is, therefore a needfor a safe and effective way to induce sterilization with a retainedoption of reversibility.

[0078] Catheters to determine the patency of fallopian tubes have beendeveloped, for example by Conceptus Inc., San Carlos, Calif. Ultrasonicinspection for determining the patency of fallopian tubes is awell-known procedure. In accordance with one aspect of the presentinvention, deswollen hydrogel plug may be inserted intrauterally intothe fallopian tubes. When the plugs rehydrate, they occlude thefallopian tubes and readily effect sterilization.

[0079] The use of substantially dehydrated hydrogels may permit suchhydrogel plugs to be deployed in a doctor's office setting, without theneed for anesthesia. If fertility is to be restored later, the hydrogelplugs may be comprise a biodegradable material that undergoes naturaldegradation in the physiological environment. Alternatively, thehydrogel plugs may be removed by administration of a solvating agent, orby mechanical removal, and the patency of the tubes restored andconfirmed by ultrasound.

[0080] 7. Sphincter Augmentation

[0081] It is estimated that at least 30 million Americans suffer fromurinary incontinence. Urinary incontinence may be either temporary orpermanent, and result from physiologic or neurologic deficits. Femalestress incontinence, i.e., the loss of urine during everyday activitiessuch as laughing, sneezing, coughing, etc., is the most common type ofincontinence, and generally responds better to surgery than topreviously known drug therapies.

[0082] Several surgical approaches have been adopted for the correctionof female stress incontinence including urethral slings, bladder necksuspensions, and artificial sphincter implantation. A recent approach tosphincter augmentation uses an injectable collagen as a urethral bulkingagent to correct intrinsic sphincter deficiency. Unfortunately, it hasbeen observed that the collagen is resorbed in up to 20% of women within9 months. Because the procedure is conducted in a minimally invasivefashion, it provides an attractive alternative to intraoperativesolutions. There remains, however, a need for a more permanent way toaugment the urinary sphincter with a percutaneously administeredbiocompatible in-situ formed bulking agent and that does not raise posethe safety risks associated with collagen.

[0083] In accordance with another aspect of the present invention,substantially dehydrated hydrogels may be percutaneously implanted intothe urethral sphincter to create an elastic and tissue-like bulk thatlasts several years. Any of the variety of hydrogels describedhereinabove have the persistence and in vivo biocompatibilitycharacteristics to be suitable for this process.

[0084] A similar approach also may be used to correct other sphincterdeficiencies. For example, the gastro-esophageal sphincter may bepercutaneously augmented to reduce gastric reflux. The pyloric sphincteralso may be percutaneously augmented to reduce “dumping” problemsassociated with intestinal pH imbalance.

[0085] 8. Medical Device Coatings

[0086] In accordance with another aspect of the present invention,substantially dehydrated hydrogel may be used to coat a medical device,so that hydration of the coating enables the medical device to becomeanchored in place to prevent migration. For example, stent grafts arewire mesh type devices that are used in conjunction with a textile typewoven, knit, or film type material. The wire framework mechanically holda lumen, e.g., an artery, open, while the textile, fabric, or filmprovides a lumen through which fluids may flow. This approach has beensuccessfully used in treating aneurysms, such as abdominal aorticaneurysms.

[0087] A significant shortcoming of previously known stent graftssystems, however, has been the leakage of blood around the stent graft.This bypass flow often causes the aneurysm to further increase in size,and may lead to eventual rupture.

[0088] In accordance with the principles of the present invention, asubstantially dehydrated hydrogel coating is disposed on the exteriorsurface of the textile, fabric, or film of the stent graft. Whendeployed in a body lumen, the coating hydrates in the presence of bloodand tightly wedges the stent graft in position. In addition, as thehydrogel hydrates it causes the stent graft to closely conform to theboundaries of the vessel, so that the blood leakage around the stentgraft may be reduced.

[0089] 9. Delivery of Drugs and Therapeutic Entities

[0090] Often the reason for performing a biopsy is the presence of asuspected tumor or other mass of diseased tissue. After confirmation ofthe biopsy identity, it may be desirable to place a therapeutic agent atthe site of suspected disease. The self-anchoring swellable hydrogelarticles of the present invention may enable the delivery of therapeuticentities to such sites through the same channel as the instrument thatis used to perform the biopsy (or with an instrument having a similarprofile).

[0091] Optionally, a hydrogel plug, such as described hereinabove, mayinclude one or more biologically-active agents and elute the agent toadjacent or distant tissues and organs in the animal.Biologically-active agents suitable for use include, for example,medicaments, drugs, or other suitable biologically-, physiologically-,or pharmaceutically-active substances that provide local or systemicbiological, physiological or therapeutic effect in the body of an animalincluding a mammal.

[0092] Water-soluble drugs that may be incorporated within the hydrogelarticles of the present include, for example, peptides having biologicalactivities, other antibiotics, antitumor agents, antipyretics,analgesics, anti-inflammatory agents, antitussive expectorants,sedatives, muscle relaxants, antiepileptic agents, antiulcer agents,antidepressants, antiallergic agents, cardiotonics, antiarrhythmicagents, vasodilators, hypotensive diuretics, antidiabetic agents,anticoagulants, hemostatics, antituberculous agents, hormonepreparations, narcotic antagonists, bone resorption inhibitors,angiogenesis inhibitors and the like.

[0093] Examples of the foregoing antitumor agents include bleomycinhydrochloride, methotrexate, actinomycin D, mitomycin C, vinblastinesulfate, vincristine sulfate, daunorubicin hydrochloride, adriamycin,neocarzinoszatin, cytosine arabinoside, fluorouracil,tetrahydrofuryl-5-fluorouracil krestin, picibanil, lentinan, levamisole,bestatin, azimexon, glycyrrhizin, poly I:C, poly A:U, poly ICLC,cisplatin and the like.

[0094] The biologically-active agent may be soluble in the polymersolution to form a homogeneous mixture, or insoluble in the polymersolution to form a suspension or dispersion. Upon implantation, thebiologically-active agent preferably becomes incorporated into theimplant matrix. As the matrix degrades over time, thebiologically-active agent is released from the matrix into the adjacenttissue fluids, preferably at a controlled rate. The release of thebiologically-active agent from the matrix may be varied, for example, bythe solubility of the biologically-active agent in an aqueous medium,the distribution of the agent within the matrix, the size, shape,porosity, solubility and biodegradability of the implant matrix, and thelike.

[0095] The biologically-active agent may stimulate a biological orphysiological activity with the animal. For example, the agent may actto enhance cell growth and tissue regeneration, function in birthcontrol, cause nerve stimulation or bone growth, and the like. Examplesof useful biologically-active agents include a substance, or metabolicprecursor thereof, that promotes growth and survival of cells andtissues, or augments the functioning of cells, as for example, a nervegrowth promoting substance such as a ganglioside, a nerve growth factor,and the like; a hard or soft tissue growth promoting agent such asfibronectin (FN), human growth hormone (HGH), protein growth factorinterleukin-1 (IL-1), and the like; a bone growth promoting substancesuch as hydroxyapatite, tricalcium phosphate, and the like; and asubstance useful in preventing infection at the implant site, as forexample, an antiviral agent such as vidarabine or acyclovir, anantibacterial agent such as a penicillin or tetracycline, andantiparasitic agent such as quinacrine or chloroquine.

[0096] Suitable biologically-active agents for use in the presentinvention also include anti-inflammatory agents such as hydrocortisone,prednisone and the like; antibacterial agents such as penicillin,cephalosporins, bacitracin and the like; antiparasitic agents such asquinacrine, chloroquine and the like; antifungal agents such asnystatin, gentamicin, and the like; antiviral agents such as acyclovir,ribavirin, interferons and the like; antineoplastic agents such asmethotrexate, 5-fluorouracil, adriamycin, tumor-specific antibodiesconjugated to toxins, tumor necrosis factor, and the like; analgesicagents such as salicylic acid, acetaminophen, ibuprofen, flurbiprofen,morphine and the like; local anesthetics such as lidocaine, bupivacaine,benzocaine and the like; vaccines such as hepatitis, influenza, measles,rubella, tetanus, polio, rabies and the like; central nervous systemagents such as a tranquilizer, B-adrenergic blocking agent, dopamine andthe like; growth factors such as colony stimulating factor,platelet-derived growth factors, fibroblast growth factor, transforminggrowth factor B, human growth hormone, bone morphogenetic protein,insulin-like growth factor and the like; hormones such as progesterone,follicle stimulating hormone, insulin, somatotropins and the like;antihistamines such as diphenhydramine, chlorphencramine and the like;cardiovascular agents such as digitalis, nitroglycerine, papaverine,streptokinase and the like; vasodilators such as theophylline, niacin,minoxidil, and the like; and other like substances.

[0097] Therapeutic agents that may be delivered may include for example,physiologically active materials or medicinal drugs (such as agentsaffecting central nervous system, antiallergic agents, cardiovascularagents, agents affecting respiratory organs, agents affecting digestiveorgans, hormone preparations, agents affecting metabolism, antitumoragents, antibiotic preparations, chemotherapeutics, antimicrobials,local anesthetics, antihistaminics, antiphlogistics, astringents,vitamins, antifungal agents, peripheral nervous anesthetics,vasodilators, crude drug essences, tinctures, crude drug powders,hypotensive agents, and the like).

[0098] The terms “cytokine” and “growth factor” are used to describebiologically active molecules and active peptides (which may be eithernaturally occurring or synthetic) that aid in healing or regrowth ofnormal tissue, including growth factors and active peptides. Thefunction of cytokines is two-fold: 1) to incite local cells to producenew collagen or tissue, or 2) to attract cells to the site in need ofcorrection. As such, cytokines and growth factors serve to encourage“biological anchoring” of the implant within the host tissue. Aspreviously described, the cytokines may be admixed with the conjugate orchemically coupled to the conjugate.

[0099] For example, one may incorporate cytokines such as interferons(IFN), tumor necrosis factors (TNF), interleukins, colony stimulatingfactors (CSFs), or growth factors such as osteogenic factor extract(OFE), epidermal growth factor (EGF), transforming growth factor (TGF)alpha, TGF-β_(including any combination of TGF-βs), TGF-β1, TGF-β2,platelet derived growth factor (PDGF-AA, PDGF-AB, PDGF-BB), acidicfibroblast growth factor (FGF), basic FGF, connective tissue activatingpeptides (CTAP), β-thromboglobulin, insulin-like growth factors,erythropoietin (EPO), nerve growth factor (NGF), bone morphogenicprotein (BMP), osteogenic factors, and the like.

[0100] The hydrogels of the present invention also may providecontrolled delivery of various antibiotics, including, for example,aminoglycosides, macrolides such as erythromycin, penicillins,cephalosporins and the like; anesthetic/analgesic delivery pre-or postsurgery or to treat pain using such agents as amide-type localanesthetics like lidocaine, mepivacaine, pyrrocaine, bupivacaine,prilocaine, etidocaine, or the like; and local controlled delivery ofnon-steroidal anti-inflammatory drugs such as ketorolac, naproxen,diclofenac sodium and flurbiprofen.

[0101] In certain forms of therapy, the same delivery system, i.e.,hydrogel article, may be used to deliver combinations of agents/drugs toobtain an optimal effect. Thus, for example, an antibacterial and ananti-inflammatory agent may be combined in a single polymer to providecombined effectiveness.

[0102] Particular water-soluble polypeptides that may be used in thehydrogel articles of the present invention include, for example,oxytocin, vasopressin, adrenocorticotrophic hormone (ACTH), epidermalgrowth factor (EGF), transforming growth factor antagonists, prolactin,luliberin or luteinizing hormone releasing hormone (LH-RH), LH-RHagonists or antagonists, growth hormone, growth hormone releasingfactor, insulin, somatostatin, bombesin antagonists, glucagon,interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin,calcitonin, enkephalins, endomorphins, angiotensins, renin, bradykinin,bacitracins, polymyzins, colistins, tyrocidin, gramicidines, andsynthetic analogues and modifications and pharmaceutically-activefragments thereof, monoclonal antibodies and soluble vaccines.

[0103] Other beneficial drugs are known in the art, as described inPharmaceutical Sciences, by Remington, 14th Ed., Mack Publishing Co.(1979); The Drug, The Nurse, The Patient, Including Current DrugHandbook, by Falconer et al., Saunder Company (1974-76); and MedicinalChemistry, 3rd Ed., Vol. 1 and 2, by Burger, Wiley-Interscience Co.

[0104] The hydrogel polymers of the present invention may be designed torelease appropriate encapsulated, or uncapsulated, growth factors,including epidermal growth factors, human platelet derived TGF-B,endothelial cell growth factors, thymocytic-activating factors, plateletderived growth factors, fibroblast growth factor, fibronectin orlaminin.

[0105] Useful release rate modification agents may be dissolved ordispersed within the hydrogel material, and include, for example,organic substances that are water-soluble, water-miscible, orwater-insoluble (i.e., water immiscible), with water-insolublesubstances preferred. The release rate modification agent preferably isan organic compound that substitutes as the complementary molecule forsecondary valence bonding between polymer molecules, and increases theflexibility and ability of the polymer molecules to slide past eachother. Such an organic compound preferably includes a hydrophobic and ahydrophilic region so as to effect secondary valence bonding.Preferably, the release rate modification agent is compatible with thecombination of polymers and solvent used to formulate polymer solution.It is further preferred that the release rate modification agent be apharmaceutically-acceptable substance.

[0106] Useful release rate modification agents include, for example,fatty acids, triglycerides, other like hydrophobic compounds, organicsolvents, plasticizing compounds and hydrophilic compounds. Suitablerelease rate modification agents include, for example, esters of mono-,di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, methylacetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutylphthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate,dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyltriethyl citrate, glycerol triacetate, di(n-butyl) sebecate, and thelike; polyhydroxy alcohols, such as propylene glycol, polyethyleneglycol, glycerin, sorbitol, and the like; fatty acids; triesters ofglycerol, such as triglycerides, epoxidized soybean oil, and otherepoxidized vegetable oils; sterols, such as cholesterol; alcohols, suchas C₆-C₁₂ alkanols, 2-ethoxyethanol, and the like.

[0107] The release rate modification agent may be used singly or incombination with other such agents. Suitable combinations of releaserate modification agents include, for example, glycerin/propyleneglycol, sorbitol/glycerine, ethylene oxide/propylene oxide, butyleneglycol/adipic acid, and the like. Preferred release rate modificationagents include dimethyl citrate, triethyl citrate, ethyl heptanoate,glycerin, and hexanediol.

EXAMPLES Example 1 Formation of Deswollen Hydrogel Rods

[0108] Hydrogels may be made using a poly(ethylene glycol) diacrylatemacromonomer (M.W. 20,000) at a concentration of 10%. 3 μl/ml of aphotoinitiator solution, such as Irgacure 651, available from CibaSpecialty Chemicals Corp., Switzerland, dissolved in N-vinylpyrrolidinone at a concentration of 0.6 g/ml) is added to the macromersolution. The solution may be injected into hollow glass tubes with aninner diameter of 4 mm and illuminated with ultraviolet light from aBlak Ray B-100A lamp for 1 min. The polymerized rods are then extrudedfrom the glass tubes and allowed to dry in an oven at 60° C. for 24 hrs.At the end of this period the rods should have substantially shrunk inoverall size. When placed in an aqueous environment (such asphysiological saline) the rods should hydrate within 15-30 minutes toseveral times the dried size.

Example 2 Use of Hydrogel Rods to Seal Parenchymal Luna Tissue

[0109] A freshly explanted pig lung is cored to retrieve a biopsy oflung parenchymal tissue using a side cutting biopsy needle (CookIncorporated, Bloomington, Ind.). On inflation of the lung with anambulatory bag an airleak should be evident at the site of the needlebiopsy. A rod-shaped hydrogel article prepared according to Example 1 isplaced within the site of the needle puncture. The natural tissue fluidsand moisture present in the needle puncture will cause the driedhydrogel to rehydrate over a few minutes to effectively plug theairleak. On subsequent inflation, no airleak should be evident and therod of hydrogel should be firmly lodged within the needle track.

Example 3 Enhancement of Rate of Hydration

[0110] It is possible to enhance the swelling rate by making the driedhydrogel hypertonic by the addition of water soluble salts or otheragents, including solvents or low molecular weight excipients oroligomers. Such agents rapidly dissolve in an aqueous setting andgenerate an osmotic driving force that accelerates the hydrationprocess.

Example 4 Further Enhancement of Rate of Hydration

[0111] Macro- or microporosity or surface texture may be created in thehydrogels to increase the surface area for ingress of aqueous fluids,thereby enhancing hydration or control of hydration. Pores formed in thedried hydrogel may create capillary forces that, i.e., a sponge-likeeffect, to cause rapid absorption of water and concomitant rapidexpansion and deployment of the hydrogel.

Example 5 Further Enhancement of Rate of Hydration

[0112] The molecular weight between crosslinks may be used as a measureto control the rate of hydration. Thus, hydrogels may be prepared asdescribed in Example 1 with PEG diacrylate macromers of varyingmolecular weights. The lower molecular weight macromers should yield amore rapid hydration, while the higher molecular weigh macromers shouldyield a slower hydration. This result obtains because the longersegments in between crosslinks that take longer to unravel completely.This phenomena also may lead to a greater total hydration for the highermolecular weight hydrogels compared to the lower molecular weighthydrogels.

Example 6 Use of Natural Hydrogel Materials

[0113] A sheet of a hydrogel forming natural material, such asSEPRAFILM™, marketed by Genzyme Corporation, Cambridge, Mass., istrimmed to form a piece approximately 2 cm square. The piece is rolledfrom one edge to the other to form a “carpet roll”. The roll then may beinserted into A needle biopsy track, as described in Example 2.Hydration of the sheet over a few minutes is expected to resulted in aneffective sealing of the site of airleak. Since the SEPRAFILM™ materialis known to be bioabsorbed over a few weeks, it is expected that, invivo, the lung tissues will heal around this material as it undergoesbioabsorption, thus forming a permanent seal even after absorption ofthe material.

Example 7 Use of a Suture Embedded Within the Hydrogel

[0114] A hydrogel rod is formed as described in Example 1, except thatsuture material (e.g., 3-0 VICRYL®, available from Ethicon, Inc., NewBrunswick, N.J.) is placed within the macromer solution in a hollowglass tube that has an inner diameter of 1.5 cm. The suture may beplaced within the macromer solution prior to polymerization, so that thehydrogel formed by polymerization contains the distal end of the sutureembedded in it, while the proximal end of the suture is free formanipulation. When dried, the suture should be firmly embedded withinthe hydrogel rod, enabling the rod of hydrogel to be easily manipulatedusing the suture.

Example 8 Use of a Suture Embedded Hydrogel as a Bone Plug

[0115] A rod of dried hydrogel that contains an embedded suture isprepared as described in Example 7. A lamb femur bone is obtained froman abattoir. The distal 5 cm of the bone may be sawed off to expose theintramedullary canal. The intramedullary canal is drilled to simulate aprocedure wherein a hip stem is implanted and fixed with a bone cement.The rod of dried hydrogel may be maneuvered 3 cm deep within theintramedullary canal until satisfactory placement depth is obtained bymeasuring the suture length remaining outside the femur.

[0116] Saline solution then is instilled within the intramedullary canaland the hydrogel allowed to hydrate until it is found to have formed anadequate friction fit within the bone. At this stage the suture may beeasily retrieved, because its holding strength within the hydrated gelshould be lower than that in the dried hydrogel. Subsequent instillationof bone cement within the cavity may be used to verify that an effectiveplugging of the intramedullary canal has been achieved.

Example 9 Use of a Hydrogel as a Cervical Canal Plug

[0117] A hydrogel plug selected in accordance with the principles of thepresent invention advantageously may be used to plug a cervical canalfollowing a tear in the amniotic membrane, which otherwise might lead toa forced pre-term birth. A plug about 3-4 mm in diameter is used toblock the cervical opening to prevent fluid drainage or leakage. Theplug should fall out when the cervix dilates naturally for normal birthand then may be easily removed.

Example 10 Use of a Hydrogel Coating on Sutures

[0118] A braided suture material (5-0 Vicryl, available from EthiconInc., New Brunswick, N.J.) is dipped in the photopolymerizable macromersolution described in Example 1. Excess macromer solution may be removeduntil a thin coating about 50-100 μm remains. The suture then is exposedto long wave ultraviolet light to polymerize the hydrogel around thesuture material. The suture is allowed to dry in an oven at 5° C.overnight.

[0119] An arterial anastamosis of a porcine carotid artery may beperformed using either the coated suture or, as a control, uncoatedsuture material. The arteries are perfused with saline at a pressure of120 mm Hg for 15 minutes with saline that contains a dye (methyleneblue, 0.2 mg/ml). Initially, both anastamoses should be found to oozethrough the suture line needle holes. This is expected, because theneedle typically has a larger diameter than the suture, resulting in ahole that is larger in size than the suture left behind in the tissue.Within 5 minutes, the coated suture line should have sealed the needleholes due to the hydration of the coating, while the control suture lineshould continue to ooze.

Example 11 Use of a Hydrogel Plug for Occlusive Sterilization

[0120] Occlusion of lumens of the reproductive systems may be effectedto accomplish male/female sterilization. For instance, the fallopiantubes of a woman may be occluded to obstruct the path of the egg, whilein men the vas deferens may be occluded to interrupt the passage ofsperm through the spermatic duct. Such occlusion of lumens may beaccomplished using rods of dried up hydrogels that are placed within thelumen and are allowed to rehydrate in the presence of moisture (in thebody), increase in volume, and gradually occlude the lumen.

[0121] In order to prevent migration of the hydrogel plugs, thediameters of the hydrogel plugs at equilibrium hydration may be selectedto be larger than the lumen to be occluded. The hydrogel rods also mayinclude a radio-opaque contrast agent to assist in placing the plugs.Further, the hydrogel plugs may be formed from absorbable hydrogels, toprovide reversible sterilization.

[0122] Alternatively, alginate-based gels that have been crosslinkedwith calcium may be used to form hydrogel plugs. Such plugs may bereinforced with an interior mesh or matrix and include a short anchoringsuture. The hydrogel plugs may be dried (or freeze dried to allow rapidrehydration), and would swell upon placement within the lumen to occludethe lumen. For reversal of sterilization, a solution of citric acid maybe administered intrauterally to redissolve the plugs and restorepatency, as confirmed, for example, by dye instillation.

Example 12 Use of a Hydrogel Plug to Close a Bronchial Fistula

[0123] A hydrogel rod is formed as described in Example 8, except thatthe rod is formed in a mold 5 mm in diameter and has a 50 cm long sutureembedded in it. The hydrogel is dried to a diameter of about 1.5 mm. Thehydrogel may be placed in a catheter comprising a hollow flexible tubewith a distal opening and a proximal end that remains outside thepatient. The distal end may be maneuvered through the operating channelof a bronchoscope and into the bronchial tree to implant the hydrogelrod.

[0124] In an explanted porcine lung, a fistula may be created byincising a segmental bronchus in the left lower lobe. Airleaks should beapparent when the lung is forcibly ventilated with an ambulatory bag.Using a 3 mm flexible bronchoscope, the segmental bronchus is visualizedand the hydrogel is ejected from the distal end of the catheter using apusher or a guidewire. The suture attached to the hydrogel rod is usedin conjunction with the guidewire to achieve accurate placement.Secretions present within the bronchial tree should enable the hydrogelto hydrate and expand. After a 10 minute period, the hydrogel should befirmly lodged within the bronchiole. The suture may now be detached andthe bronchoscope withdrawn. When ventilation is resumed, after about 15minutes, the bronchus should be effectively occluded and no airleakshould be evident.

Example 13 Use of Hydrogel to Seal Cerebrospinal Fluid Leaks

[0125] Surgical treatment of tumors near the skull base generally entaila transsphenoidal approach, wherein surgery is performed through a nasalcavity. A common complication of this type of surgical procedure is acerebrospinal fluid leak due to rupture of the sellar floor. Persistentrhinorrhea may result, which is considered a major complication ofsurgery and may lead to life-threatening infections. Typically, at theend of such surgeries abdominal fat is harvested and used to plug thenasal cavity. There is therefore a need for a synthetic material thatcould be used for this purpose to obviate the surgical procedure toharvest the fat and reduce morbidity to the patient.

[0126] In accordance with the principles of the present invention, ahydrogel plug prepared as described in Example 6 may be introducedtransnasally and allowed to hydrate and effectively plug the nasalcavity, thus preventing leakage of cerebrospinal fluid.

Example 14 Increased Rate of Hydration by Micropores

[0127] The process of freeze drying or lyophilization creates macro andmicropores within a dried hydrogel. These pores allow more rapid ingressof water and other aqueous fluids into the hydrogel, and cause the dryhydrogel to hydrate at a rate faster than that of an oven-driedhydrogel. The phenomenon may be illustrated by making two identicalhydrogels as described in Example 1. The first hydrogel is allowed todry in an oven at 50° C. overnight; the other hydrogel is frozen at −40°C. and then allowed to gradually freeze dry over a period of 1 day. Thehydrogels obtained then are allowed to rehydrate in physiologicalsaline. The normalized weights of the two hydrogels may be compared aswet weight/dry weight over a period of time. It is expected that themacroporous lyophilized dry hydrogel hydrates at a substantially fasterrate than the oven-dried hydrogel.

Example 15 Use of Osmolality Enhancing Agents to Speed Hydration

[0128] The driving force of aqueous fluid ingress in a hydrogel isprimarily the osmotic potential difference between the collapsed driedor non-equilibrium hydrated hydrogel. Thus, the rate of fluid uptake ofhydration may be enhanced by incorporating osmolality enhancing agentsin the hydrogel.

[0129] A macromer solution is formulated as described in Example 1 anddivided into two aliquots. In the first aliquot 200 mg/ml of NaCl isadded; nothing is added further to the other aliquot. Rod shapedhydrogels are prepared from both formulations as described in Example 1.The hydrogel rods then are allowed to further hydrate by placing them ina physiological salt solution, without first drying the rods. It isexpected that the hydrogel containing the NaCl will hydrate at asignificantly faster rate to its equilibrium level than the controlhydrogel.

Example 16 Use of a Wetting Agent or Consolute to Speed Hydration

[0130] In the experiment of Example 14, hydration of the lyophilized dryhydrogel is expected to be somewhat impeded by the presence of airbubbles present in the macro and micropores. PEG 600 may be added to themacromer solution described in Example 1 at a concentration of 5 mg/mland a hydrogel further formed and lyophilized as described in Example14. The lyophilized rod of dry hydrogel is expected to be more pliable.When the hydrogel rod is rehydrated in normal saline, it is expectedthat the hydrogel including the PEG 600 as a wetting agent willrehydrate somewhat faster than the rod of lyophilized hydrogel that didnot have any wetting agent incorporated.

[0131] Also, during the rehydration, it is expected that few air bubbleswill be observed in the hydrogel that contains the wetting agent. Themechanism for this increased rate of hydration is not readily apparentand may be due to the improved wetting characteristics of the hydrogel,the more expanded structure of the hydrogel in the water depleted form,or reduced interfacial tension between the water and the air presentwithin the micropores, thus allowing easy access to the interiorstructure of the hydrogel. That the mechanism is unknown, however, doesnot reflect on the utility of, or otherwise limit, the invention.

[0132] Modifications and variations of the present invention, themacromers and polymeric compositions and methods of use thereof, will beapparent to those skilled in the art from the foregoing detaileddescription. While preferred illustrative embodiments of the inventionare described above, it will be apparent to one skilled in the art thatvarious changes and modifications may be made therein without departingfrom the invention and it is intended in the appended claims to coverall such changes and modifications which fall within the true spirit andscope of the invention.

What is claimed is:
 1. A method for anchoring an implant in a lumen orvoid in a body comprising: providing a member comprising apharmaceutically acceptable crosslinked hydrogel, the member having afirst state wherein the hydrogel is at substantially less than anequilibrium level of hydration, and a second state wherein the hydrogelis substantially at the equilibrium level of hydration, the memberundergoing volumetric expansion while transitioning to the second state;positioning the member in the lumen or void in the first state; andhydrating the member to transition the hydrogel to the second state sothat the member undergoes sufficient volumetric expansion to becomeanchored within and occlude the lumen or void.
 2. The method of claim 1wherein providing a member comprising a pharmaceutically acceptablecrosslinked hydrogel comprises providing a member comprising apharmaceutically acceptable crosslinked hydrogel having a shape selectedfrom the group consisting of rods, spheres, blocks, sheets, tubes andirregularly shaped particles.
 3. The method of claim 1 wherein providinga member comprising a pharmaceutically acceptable crosslinked hydrogelfurther comprises providing a member comprising a pharmaceuticallyacceptable crosslinked hydrogel that is biodegradable in vivo.
 4. Themethod of claim 1 wherein providing a member comprising apharmaceutically acceptable crosslinked hydrogel further comprisesproviding a member comprising a pharmaceutically acceptable crosslinkedhydrogel having a tensile strength in excess of 10 kPa.
 5. The method ofclaim 1 wherein providing a member comprising a pharmaceuticallyacceptable crosslinked hydrogel further comprises: providing a membercomprising a pharmaceutically acceptable crosslinked hydrogel containinga therapeutic bioactive molecule; and after hydrating the member,eluting the therapeutic bioactive molecule from the hydrogel.
 6. Themethod of claim 1 wherein the lumen or void is a needle track formed bya biopsy device and positioning the member in the lumen or voidcomprises positioning the member in the needle track after retrieval ofa biopsy sample.
 7. The method of claim 1 wherein the lumen or void is anaturally occurring body passageway and positioning the member in thelumen or void comprises positioning the member in the naturallyoccurring body passageway.
 8. The method of claim 7 wherein thenaturally occurring body passageway forms a portion of reproductivesystem of a mammal and hydrating the member renders the mammal sterile.9. The method of claim 8 wherein the naturally occurring body passagewayis a fallopian tube and positioning the member comprises inserting themember into the fallopian tube using a catheter.
 10. The method of claim8 wherein providing a member comprising a pharmaceutically acceptablecrosslinked hydrogel further comprises providing a member comprising apharmaceutically acceptable crosslinked hydrogel that is biodegradablein vivo.
 11. The method of claim 1 wherein the lumen or void is anarteriovenous malformation and positioning the member in the lumen orvoid comprises positioning the member in the arteriovenous malformation.12. The method of claim 1 wherein lumen or void provides an access siteto a vessel through a puncture, the method further comprising: providinga pledget coupled to the member; positioning the pledget to occlude thepuncture, wherein hydrating the member to transition the hydrogel to thesecond state causes the member to become lodged within and occlude thelumen or void while retaining the pledget in position.
 13. The method ofclaim 1 wherein the lumen or void is a bone canal and positioning themember in the lumen or void comprises positioning the member in the bonecanal.
 14. The method of claim 1 wherein providing a member comprising apharmaceutically acceptable crosslinked hydrogel further comprises:providing a first hydrogel component; providing a second hydrogelcomponent; instilling the first and second hydrogel components into thelumen or void; and polymerizing the first and second hydrogel componentsto form the member.
 15. The method of claim 14 wherein the firsthydrogel component comprises a foaming agent, the method furthercomprising: activating the foaming agent while polymerizing the firstand second hydrogel components to create a controlled amount of porosityin the hydrogel.
 16. The method of claim 1 wherein providing a membercomprising a pharmaceutically acceptable crosslinked hydrogel furthercomprises providing a member comprising a pharmaceutically acceptablecrosslinked hydrogel that, in the first state, contains an excipientthat assists in rehydration.
 17. A method of augmenting tissue in amammalian body comprising: providing a member comprising apharmaceutically acceptable crosslinked hydrogel, the member having afirst state wherein the hydrogel is at substantially less than anequilibrium level of hydration, and a second state wherein the hydrogelis substantially at the equilibrium level of hydration, the memberundergoing volumetric expansion while transitioning to the second state;creating a cavity in the tissue; positioning the member in the cavity inthe first state; and hydrating the member to transition the hydrogel tothe second state so that the member expands the tissue and becomeslodged within the cavity.
 18. The method of claim 17 wherein whereinproviding a member comprising a pharmaceutically acceptable crosslinkedhydrogel comprises providing a member comprising a pharmaceuticallyacceptable crosslinked hydrogel having a shape selected from the groupconsisting of rods, spheres, blocks, sheets, tubes and irregularlyshaped particles.
 19. The method of claim 17 wherein providing a membercomprising a pharmaceutically acceptable crosslinked hydrogel furthercomprises providing a member comprising a pharmaceutically acceptablecrosslinked hydrogel that is biodegradable in vivo.
 20. The method ofclaim 17 wherein providing a member comprising a pharmaceuticallyacceptable crosslinked hydrogel further comprises: providing a membercomprising a pharmaceutically acceptable crosslinked hydrogel containinga therapeutic bioactive molecule; and after hydrating the member,eluting the therapeutic bioactive molecule from the hydrogel into tissuesurrounding the cavity.
 21. The method of claim 17 wherein the cavity isformed in sphincter tissue and hydrating the member augments the volumeof a sphincter.
 22. The method of claim 17 wherein providing a membercomprising a pharmaceutically acceptable crosslinked hydrogel furthercomprises: providing a first hydrogel component; providing a secondhydrogel component; instilling the first and second hydrogel componentsinto the cavity; and polymerizing the first and second hydrogelcomponents to form the member.
 23. The method of claim 22 wherein thefirst hydrogel component comprises a foaming agent, the method furthercomprising: activating the foaming agent while polymerizing the firstand second hydrogel components to create a controlled amount of porosityin the hydrogel.
 24. The method of claim 17 wherein providing a membercomprising a pharmaceutically acceptable crosslinked hydrogel furthercomprises providing a member comprising a pharmaceutically acceptablecrosslinked hydrogel that, in the first state, contains an excipientthat assists in rehydration.
 25. A method of anchoring a medical devicewithin a mammalian body comprising: providing an medical device;providing a pharmaceutically acceptable crosslinked hydrogel, thehydrogel having a first state wherein the hydrogel is at substantiallyless than an equilibrium level of hydration, and a second state whereinthe hydrogel is substantially at the equilibrium level of hydration, thehydrogel undergoing volumetric expansion while transitioning to thesecond state; coating an exterior surface of the medical device with thehydrogel; positioning the medical device in the mammalian body in thefirst state; and hydrating the hydrogel to transition the hydrogel tothe second state so that the hydrogel undergoes volumetric expansion andanchors the medical device within the mammalian body.
 26. The method ofclaim 25 wherein providing a pharmaceutically acceptable crosslinkedhydrogel further comprises providing a pharmaceutically acceptablecrosslinked hydrogel that is biodegradable in vivo.
 27. The method ofclaim 25 wherein providing a pharmaceutically acceptable crosslinkedhydrogel further comprises: providing a pharmaceutically acceptablecrosslinked hydrogel containing a therapeutic bioactive molecule; andafter hydrating the hydrogel, eluting the therapeutic bioactive moleculefrom the hydrogel into the mammalian body.
 28. The method of claim 25wherein providing a pharmaceutically acceptable crosslinked hydrogelfurther comprises providing a pharmaceutically acceptable crosslinkedhydrogel that, in the first state, contains an excipient that assists inrehydration.
 29. The method of claim 25 wherein the medical devicecomprises a suture disposed through a needle hole and hydrating thehydrogel causes the hydrogel to seal the needle hole.
 30. The method ofclaim 25 wherein the medical device comprises a stent graft system andhydrating the hydrogel causes the hydrogel to seal the stent graftvessel against bypass flow.